Antonella Palla

Gravity dependence of ocular drift in patients with cerebellar downbeat nystagmus

Downbeat nystagmus is a frequent ocular motor sign in patients with lesions of the vestibulocerebellum. The upward drift in downbeat nystagmus is a combination of a gaze‐evoked drift, due to an impaired vertical neural integrator, and a velocity bias. Using a three‐dimensional turntable, we analyzed the influence of gravity on these two mechanisms. Patients with cerebellar downbeat nystagmus (n = 6) and healthy subjects (n = 12) were placed in various whole‐body positions along the roll, pitch, and oblique vertical planes of the head. Ocular drift was monitored with scleral search coils. Although there was no gravity dependence of the vertical gaze‐evoked drift, the vertical velocity bias consisted of two components: a gravity‐dependent component that sinusoidally modulated as a function of body position along the pitch plane, and a gravity‐independent component that was directed upward. The combination of the two components led to an overall drift that was minimal in supine and maximal in prone position. In healthy subjects, only the gravity‐dependent component was present, but in a scaled‐down manner. Our results suggest that the intact vestibulocerebellum minimizes an overacting otolith‐ocular reflex elicited by pitch tilt and cancels an inherent upward ocular drift that is independent of gravity‐modulated otolith signals.

The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia

Xenomelia is the oppressive feeling that one or more limbs of ones body do not belong to ones self. We present the results of a thorough examination of the characteristics of the disorder in 15 males with a strong desire for amputation of one or both legs. The feeling of estrangement had been present since early childhood and was limited to a precisely demarcated part of the leg in all individuals. Neurological status examination and neuropsychological testing were normal in all participants, and psychiatric evaluation ruled out the presence of a psychotic disorder. In 13 individuals and in 13 pair-matched control participants, magnetic resonance imaging was performed, and surface-based morphometry revealed significant group differences in cortical architecture. In the right hemisphere, participants with xenomelia showed reduced cortical thickness in the superior parietal lobule and reduced cortical surface area in the primary and secondary somatosensory cortices, in the inferior parietal lobule, as well as in the anterior insular cortex. A cluster of increased thickness was located in the central sulcus. In the left hemisphere, affected individuals evinced a larger cortical surface area in the inferior parietal lobule and secondary somatosensory cortex. Although of modest size, these structural correlates of xenomelia appear meaningful when discussed against the background of some key clinical features of the disorder. Thus, the predominantly right-sided cortical abnormalities are in line with a strong bias for left-sided limbs as the target of the amputation desire, evident both in our sample and in previously described populations with xenomelia. We also propose that the higher incidence of lower compared with upper limbs (∼80% according to previous investigations) may explain the erotic connotations typically associated with xenomelia, also in the present sample. These may have their roots in the proximity of primary somatosensory cortex for leg representation, whose surface area was reduced in the participants with xenomelia, with that of the genitals. Alternatively, the spatial adjacency of secondary somatosensory cortex for leg representation and the anterior insula, the latter known to mediate sexual arousal beyond that induced by direct tactile stimulation of the genital area, might play a role. Although the right hemisphere regions of significant neuroarchitectural correlates of xenomelia are part of a network reportedly subserving body ownership, it remains unclear whether the structural alterations are the cause or rather the consequence of the long-standing and pervasive mismatch between body and self.

Velocity Storage Contribution to Vestibular Self-Motion Perception in Healthy Human Subjects

Self-motion perception after a sudden stop from a sustained rotation in darkness lasts approximately as long as reflexive eye movements. We hypothesized that, after an angular velocity step, self-motion perception and reflexive eye movements are driven by the same vestibular pathways. In 16 healthy subjects (25-71 years of age), perceived rotational velocity (PRV) and the vestibulo-ocular reflex (rVOR) after sudden decelerations (90°/s(2)) from constant-velocity (90°/s) earth-vertical axis rotations were simultaneously measured (PRV reported by hand-lever turning; rVOR recorded by search coils). Subjects were upright (yaw) or 90° left-ear-down (pitch). After both yaw and pitch decelerations, PRV rose rapidly and showed a plateau before decaying. In contrast, slow-phase eye velocity (SPV) decayed immediately after the initial increase. SPV and PRV were fitted with the sum of two exponentials: one time constant accounting for the semicircular canal (SCC) dynamics and one time constant accounting for a central process, known as velocity storage mechanism (VSM). Parameters were constrained by requiring equal SCC time constant and VSM time constant for SPV and PRV. The gains weighting the two exponential functions were free to change. SPV were accurately fitted (variance-accounted-for: 0.85 ± 0.10) and PRV (variance-accounted-for: 0.86 ± 0.07), showing that SPV and PRV curve differences can be explained by a greater relative weight of VSM in PRV compared with SPV (twofold for yaw, threefold for pitch). These results support our hypothesis that self-motion perception after angular velocity steps is be driven by the same central vestibular processes as reflexive eye movements and that no additional mechanisms are required to explain the perceptual dynamics.

Recovery of the High-Acceleration Vestibulo-ocular Reflex After Vestibular Neuritis

Vestibular neuritis (VN) usually leads to a sudden gain asymmetry of the high-acceleration horizontal vestibulo-ocular reflex (VOR). We asked whether this asymmetry decreases over time indicating peripheral recovery and/or central compensation. The horizontal VOR during rapid rotational head impulses to both sides was recorded with search coils in 37 patients at different time periods (1–240 weeks) after the onset of VN. In ten patients, sequential measurements were performed. Gains of the VOR during head impulses toward the ipsilesional side significantly increased after the initial drop (average gains: < 1 week: 0.35; 1–4 weeks: 0.33; 4–40 weeks: 0.55; 40–240 weeks: 0.50). Gains on the contralesional side, however, were only slightly reduced and showed no significant change. We conclude that, in contrast to patients after hemilabyrinthectomy or unilateral vestibular neurectomy, the ocular response to ipsilesional rotations in patients after VN improves over time. This finding suggests that ipsilesional recovery is peripheral or, if central, depends on spared peripheral function. The physiology of linear and nonlinear VOR pathways predicts a considerable gain reduction for contralesional head impulses if central compensation mechanisms are not engaged. Thus, the relatively preserved gain on the contralesional side can be explained only by central “upregulation”. Apparently, for high accelerations of the head, effective central compensation after VN does not aim to balance the gains of the VOR but tries to boost the contralesional gain close to normal.

Visual Dependency and Dizziness after Vestibular Neuritis

Symptomatic recovery after acute vestibular neuritis (VN) is variable, with around 50% of patients reporting long term vestibular symptoms; hence, it is essential to identify factors related to poor clinical outcome. Here we investigated whether excessive reliance on visual input for spatial orientation (visual dependence) was associated with long term vestibular symptoms following acute VN. Twenty-eight patients with VN and 25 normal control subjects were included. Patients were enrolled at least 6 months after acute illness. Recovery status was not a criterion for study entry, allowing recruitment of patients with a full range of persistent symptoms. We measured visual dependence with a laptop-based Rod-and-Disk Test and severity of symptoms with the Dizziness Handicap Inventory (DHI). The third of patients showing the worst clinical outcomes (mean DHI score 36–80) had significantly greater visual dependence than normal subjects (6.35° error vs. 3.39° respectively, p = 0.03). Asymptomatic patients and those with minor residual symptoms did not differ from controls. Visual dependence was associated with high levels of persistent vestibular symptoms after acute VN. Over-reliance on visual information for spatial orientation is one characteristic of poorly recovered vestibular neuritis patients. The finding may be clinically useful given that visual dependence may be modified through rehabilitation desensitization techniques.

Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy.

Progressive hearing (pHL) and vestibular (pVL) loss are frequent deficits in Fabry disease (FD). Recently, enzyme replacement therapy (ERT) with human α-galactosidase A has become available. Here, we investigate the association between pHL and pVL in FD and their ERT responses. Pure tone audiometry (PTA) and head impulse testing (HIT) were administered at baseline in 47 patients (25 male, 18-0 y; 22 female, 17-4 y), of whom 24 also received caloric irrigation (CI). Of the 47 patients, 38 (24 male) were tested both before and during ERT (follow- up ≤60 months). ERT consisted of agalsidase alfa infusions. At baseline, pHL was present in 88% of males and 86% of females. Over all tested frequencies (range: 0.5- kHz), pHL was significantly (two-way ANOVA: p < 0.05) greater at higher age and in males,with largest deficits at high frequencies. When assessed with HIT, 80% of males and 77% of females had pVL. pVL was significantly greater at higher age and in males. Tested with CI, 21% of males and 0% of females had pVL. No associations among individual semicircular canal (SCC) deficits, as tested by HIT, and hearing was observed in individual ears. After ≥18 months of ERT, pVL was significantly smaller than at baseline (ANOVA for HIT: p < 0.01). In contrast, pHL remained unchanged by ERT over 60 months (p > 0.05). We conclude that pHL and pVL prevalences are similar in FD. To detect pVL, HIT is more sensitive than CI. We speculate that pHL and pVL emerge from lesions within the vestibulocochlear labyrinth, because no specific patterns of vestibulo-cochlear deficits were observed, as expected if lesions were more proximal along the inferior or superior branch of the vestibulo-cochlear nerve or labyrinthine artery. Finally, ERT stabilizes auditory and even improves vestibular function.

Eye-position dependence of three-dimensional ocular rotation-axis orientation during head impulses in humans

Abstract If horizontal saccades or smooth-pursuit eye movements are made with the line-of-sight at different elevations, the three-dimensional (3D) angular rotation axis of the globe tilts by half the vertical eye eccentricity. This phenomenon is named ”half-angle rule” and is a consequence of Listing’s law. It was recently found that the ocular rotation axis during the horizontal vestibulo-ocular reflex (VOR) on a turntable also tilts in the direction of the line-of-sight by about a quarter of the eye’s vertical eccentricity. This is surprising, since, in a ”perfect” VOR, the angular rotation axis of the eye should be independent from the position of the eye to fully compensate for the 3D angular head rotation. We asked whether this quarter-angle strategy is a general property of the VOR or whether the 3D kinematics of ocular movements evoked by vestibular stimulation would be less eye-position dependent at higher stimulus frequencies. Nine healthy subjects were exposed to horizontal head impulses (peak velocity ∼250°/s). The line-of-sight was systematically changed along the vertical meridian of a tangent screen. Three-dimensional eye and head movements were monitored with dual search coils. The 3D orientation of the angular eye-in-head rotation axis was determined by calculating the average angular velocity vectors of the initial 10° displacements. Then, the difference between the tilt angles of the ocular rotation axis during upward and downward viewing was determined and divided by the difference of vertical eccentricity (”tilt angle coefficient”). Control experiments included horizontal saccades, smooth-pursuit eye movements, and eye movements evoked by slow, passive head rotations at the same vertical eye eccentricities. On average, the ocular rotation axis during horizontal head-impulse testing at different elevations of the line-of-sight was closely aligned with the rotation axis of the head (tilt angle coefficient of pooled abducting and adducting eye movements: 0.11±0.17 SD). Values for slow head impulses, however, exceeded somewhat the quarter angle (0.33±0.12), while smooth-pursuit movements (0.50±0.09) and saccades (0.44±0.11) were closest to the half angle. These results demonstrate that the 3D orientation of the ocular rotation axis during rapid head thrusts is relatively independent of the direction of the line-of-sight and that ocular rotations elicited by head impulses are kinematically different from saccades, despite similar movement dynamics.

Vestibular neuritis: Vertigo and the high-acceleration vestibulo-ocular reflex

Patients after vestibular neuritis (VN) often report persistent dizziness and disequilibrium. We correlated persistent symptoms with sustained impairment of the high-acceleration horizontal vestibulo-ocular reflex as determined by quantitative searchcoil head-impulse testing (qHIT). In 47 patients, qHIT was recorded 0–60 months and symptoms assessed with the Yardley Vertigo Symptom Scale short form ≥ 18 months after VN onset. No correlation between the magnitude of high-acceleration vestibular impairment and the severity of vertigo symptoms was observed. The lack of a symptom-qHIT correlation suggests that defective compensation at a more rostral level in the central nervous system may be responsible for protracted symptoms in VN patients.

Is Vestibular Self-Motion Perception Controlled by the Velocity Storage? Insights from Patients with Chronic Degeneration of the Vestibulo-Cerebellum

Background The rotational vestibulo-ocular reflex (rVOR) generates compensatory eye movements in response to rotational head accelerations. The velocity-storage mechanism (VSM), which is controlled by the vestibulo-cerebellar nodulus and uvula, determines the rVOR time constant. In healthy subjects, it has been suggested that self-motion perception in response to earth-vertical axis rotations depends on the VSM in a similar way as reflexive eye movements. We aimed at further investigating this hypothesis and speculated that if the rVOR and rotational self-motion perception share a common VSM, alteration in the latter, such as those occurring after a loss of the regulatory control by vestibulo-cerebellar structures, would result in similar reflexive and perceptual response changes. We therefore set out to explore both responses in patients with vestibulo-cerebellar degeneration. Methodology/Principal Findings Reflexive eye movements and perceived rotational velocity were simultaneously recorded in 14 patients with chronic vestibulo-cerebellar degeneration (28–81yrs) and 12 age-matched healthy subjects (30–72yrs) after the sudden deceleration (90°/s2) from constant-velocity (90°/s) rotations about the earth-vertical yaw and pitch axes. rVOR and perceived rotational velocity data were analyzed using a two-exponential model with a direct pathway, representing semicircular canal activity, and an indirect pathway, implementing the VSM. We found that VSM time constants of rVOR and perceived rotational velocity co-varied in cerebellar patients and in healthy controls (Pearson correlation coefficient for yaw 0.95; for pitch 0.93, p<0.01). When constraining model parameters to use the same VSM time constant for rVOR and perceived rotational velocity, moreover, no significant deterioration of the quality of fit was found for both populations (variance-accounted-for >0.8). Conclusions/Significance Our results confirm that self-motion perception in response to rotational velocity-steps may be controlled by the same velocity storage network that controls reflexive eye movements and that no additional, e.g. cortical, mechanisms are required to explain perceptual dynamics.

Ataxia telangiectasia: a "disease model" to understand the cerebellar control of vestibular reflexes.

Experimental animal models have suggested that the modulation of the amplitude and direction of vestibular reflexes are important functions of the vestibulocerebellum and contribute to the control of gaze and balance. These critical vestibular functions have been infrequently quantified in human cerebellar disease. In 13 subjects with ataxia telangiectasia (A-T), a disease associated with profound cerebellar cortical degeneration, we found abnormalities of several key vestibular reflexes. The vestibuloocular reflex (VOR) was measured by eye movement responses to changes in head rotation. The vestibulocollic reflex (VCR) was assessed with cervical vestibular-evoked myogenic potentials (cVEMPs), in which auditory clicks led to electromyographic activity of the sternocleidomastoid muscle. The VOR gain (eye velocity/head velocity) was increased in all subjects with A-T. An increase of the VCR, paralleling that of the VOR, was indirectly suggested by an increase in cVEMP amplitude. In A-T subjects, alignment of the axis of eye rotation was not with that of head rotation. Subjects with A-T thus manifested VOR cross-coupling, abnormal eye movements directed along axes orthogonal to that of head rotation. Degeneration of the Purkinje neurons in the vestibulocerebellum probably underlie these deficits. This study offers insights into how the vestibulocerebellum functions in healthy humans. It may also be of value to the design of treatment trials as a surrogate biomarker of cerebellar function that does not require controlling for motivation or occult changes in motor strategy on the part of experimental subjects.